Presently, there is no adequate dermatological treatment for hyperpigmentary disorders, such as solar lentigines, melasma and post-inflammatory hyperpigmentation. The depigmentation market is currently serviced by marginally effective prescription and over-the-counter (xe2x80x9cOTCxe2x80x9d) products.
The principal active in OTC products is hydroquinone. It is employed at a level of 1.5% or 2%.
Prescription strength hydroquinone dermatological products contain 3% or 4% hydroquinone. Such products are irritating to the skin and can cause irreversible depigmentation. Thus there is great need for a safe and effective treatment for hyperpigmentary disorders.
Nair et al U.S. Pat. No. 5,194,247, discloses a corticosteroid free synergistic depigmentation composition containing 0.1% to 5%, by weight, 4-hydroxyanisole (xe2x80x9c4-HAxe2x80x9d) and 0 001% to 1%, by weight, of at least one retinoid selected from all-trans retinoic acid, (N-acetyl-4-aminophenyl) retinoate and 11-cis, 13-cis-12-hydroxymethyl retinoic acid-xcex94-lactone.
Nair et al U.S. Pat. No. 5,470,567, discloses a corticosteroid free synergistic composition for skin depigmentation. The composition comprises 0. 1% to 2%, by weight, 4-HA and a retinoid. The retinoid is 0.001% to 0.1%, by weight, all-trans retinoic acid; 0.001% to 0.01%, by weight, (N-acetyl-4-aminophenyl) retinoate or 0.001% to 0.1% by weight 11-cis, 13-cis-12-hydroxymethyl retinoic acid-xcex94-lactone.
Thus, the prior art appreciates the use of 4-HA and all-trans retinoic acid in treating hyperpigmentary disorders. All-trans retinoic acid is also known as Vitamin A acid and as Tretinoin. It is henceforth referred to herein asxe2x80x9cTretinoinxe2x80x9d.
U.S. Pat. No. 5,470,567, discloses testing of a solution of 1% 4-HA and 0.01% tretinoin in 98.99% PEG-8/ethanol (5:95) (see Column 6, lines 36-43). The solution was obviously freshly prepared and tested immediately thereafter. Patentees do not teach or even suggest that such solution would provide long term storage stability of tretinoin and 4-HA contained therein.
Assuming that the ethanol employed by patentees was ethanol USP (containing 5% water), patentees"" composition containing 98.99% of a 5:95 mixture of PEG-8 and ethanol, respectively, would have contained 4.7% water, an amount insufficient to solubilize other formulation ingredients found necessary by the present inventors to enable long-term storage stability of solutions containing 4-HA and tretinoin.
It should be noted that patentees in U.S. Pat. No. 5,470,567 and 5,194,247 fail to appreciate that 4-HA, in the presence of emulsifiers, degrades tretinoin contained in emulsion formations or that a 4-HA and tretinoin solution containing at least 12%, preferably at least 15%, more preferably at least 20% water, as in the present invention, will afford long-term stability of the tretinoin and 4-HA components.
Kligman et al U.S. Pat. No. 6,008,254 discloses a method of treating skin disorders with high-strength tretinoin. Patentees disclose a composition in which tretinoin is carried in a solvent vehicle. Patentees teach that Tretinoin is substantially insoluble in aqueous vehicles and therefore organic solvent vehicles are preferred. Patentees indicate that a preferred vehicle comprises from about 20 to 80%, by weight, ethanol or isopropanol with the balance being liquid glycol, preferably polyethylene glycol. The Examples illustrate a 0.25%, by weight, solution of tretinoin in a 50:50 mixture of 95% ethanol/polyethylene glycol 400.
The object of the present invention was to develop a composition comprising a solution of tretinoin and 4-HA having long term physical and chemical stability (viz. long term storage stability), as hereinafter defined, and optimal skin permeation, said composition being useful in the topical treatment of solar lentigines and related hyperpigmented lesions.
Tretinoin is known to be a very unstable drug. It can undergo thermal, oxidative and photo degradation. Because of its instability, the United States Pharmacopoeia allows up to a 35% overage for commercial 0.05% tretinoin solution formulations marketed in the United States. The British Pharmacopoeia allows a 20% overage for tretinoin solution and commercial tretinoin products in Europe are available in 0.025, 0.05, 0.1 and 0.2% strengths.
Compared to tretinoin, 4-HA is more stable, however, it can still undergo oxidative decomposition to hydroquinone and other degradation products.
Oxidation and photochemical reactions are, for the most part, one-electron reactions. Trace amounts of environmental agents can powerfully catalyze these reactions. Contamination by trace metal ions can catalyze oxidative reactions by many orders of magnitude. Even the presence of trace amounts of photosensitive agents in the excipients can cause a susceptible molecule, such as tretinoin, to undergo apparent photochemical reactions.
Oxidative degradation reactions are free radical reactions. Characteristically, many free radical reactions involve lag time or lag phase corresponding to gradual build-up of free radicals via the initial step. If the radicals produced from the initiator go into a propagative cycle, the overall loss of a drug, like tretinoin, will then follow first-order decay with respect to the drug. If chain branching occurs, as it the case of drugs containing conjugated double bonds, the overall loss of drug will be many orders of magnitude and the drug will have a very short shelf life.
Oxidative degradation kinetics involves lag time. Since, oxygen solubility in solvents, such as water and alcohol, is temperature dependent, the interpretation of temperature effects on oxidative reactions is not predictable.
The complications involved in oxidative degradation kinetics make it difficult to rely on accelerated stability data to evaluate the shelf like of tretinoin.
Tretinoin is known to undergo antioxidation. Various degradation products are produced, for example, epoxides, dioxetane, an endoperoxide and double-bond cleavage products. The oxidation process may also result in isomerization (Motto, M. G. et al, J. Chromat., 48, 1989, pages 255-262).
In general, retinoids are known to isomerize by chemical methods, with heat, and, most importantly, by the action of light.
Theoretically, each of the double bonds in retinoic acid can undergo isomerization to give mono, cis, and multiple cis isomers, resulting in a possible total of sixteen double bond isomers. Eight additional isomers are possible due to cyclization of the 7-cis isomer of retinoic acid. Thus a total of twenty four photoisomers is possible.
The chemical stability of 0.05% tretinoin in solution and gel formulations is reported in the literature (see British Pharmacopoeia, II, 1993, page 1137).
The shelf life of tretinoin in a propylene glycol-alcohol solution at 25xc2x0 C is 6.7 months. In an aqueous tretinoin gel with lauromacragol (Brig(copyright) 35s) as the solubilizing agent, the shelf like is twelve days. The shelf life of tretinoin in aqueous gels, with and without Cremophor(copyright) RH40 as a solubilizing agent, is 3 months and 10 months respectively. The stability of tretinoin is low in solubilized formulations and is influenced by the types of solubilizing agents and other excipients used in the formulations (Brisaert, M. G., et al, Pharma. Acta. Helv., 70, 1995, pages 161-166).
In an effort to develop a pharmaceutically elegant dermatological composition containing tretinoin and 4-HA and having long term storage stability (as hereinafter defined), the present inventors incorporated the tretinoin and 4-HA in cream compositions. The oil-in-water emulsion based creams broke. Most likely, this was due to the 4-HA component as it is soluble in both the oil phase and water phase. Addition of other emulsifiers and thickeners resolved the problem of physical instability of the emulsion; however, tretinoin proved to be very unstable in such formulations.
The long-term storage stable composition of the present invention comprises:
(a) 0.5 to 5% (w/v), preferably 1 to 3% (w/v), more preferably about 2% (w/v) 4-HA;
(b) 0.002 to 0.05% (w/v), preferably 0.005 to 0.02% (w/v), more preferably 0.01% (w/v) tretinoin;
(c) 2 to 10% (v/v), preferably 3 to 5% (v/v), more preferably about 4% (v/v) of a low molecular weight liquid polyethylene glycol, most preferably, PEG-8;
(d) 0.001 to 1.5% (w/v), preferably 0.003 to 1.25% (w/v), more preferably about 1% (w/v) of an antioxidant or mixture of antioxidants selected from the group consisting of butylated hydroxyanisole (xe2x80x9cBHAxe2x80x9d), butylated hydroxytoluene (xe2x80x9cBHTxe2x80x9d), ascorbic acid, ascorbyl palmitate, lecithin, norhydroguaiaretic acid, propyl gallate, a-tocopherol, sodium bisulfite, cysteine, sodium metabisulfite, thioglycerol, thioglycolic acid, and thiomersal; preferably BHT, ascorbic acid, ascorbyl palmitate and mixtures thereof; the antioxidant or mixture of antioxidants being selected so as to provide at least two of the finctions of oxygen scavenging, chain terminating and reducing;
(e) 0.001 to 0.1% (w/v), preferably 0.002 to 0.05% (w/v), more preferably 0.003 to 0.02% (w/v), most preferably about 0.015% (w/v), of a chelating agent selected from the group consisting of citric acid, disodium ethylenediamine tetraacetic acid (xe2x80x9cDisodium EDTAxe2x80x9d), phosphoric acid, tartaric acid, sorbitol, phenylalanine and mixtures thereof, preferably, citric acid, disodium EDTA and mixtures thereof;
(f) 50 to 88% (v/v), preferably 60 to 85% (v/v), more preferably 65 to 80% (v/v), most preferably, 75 to 80% (v/v), of lower alkanol, preferably isopropanol, ethanol or a mixture thereof, more preferably ethyl alcohol (USP);
(g) an acidulant in an amount sufficient to adjust the pH of the composition to from about 2.5 to about 5, preferably about 3 to about 4.5, more preferably about 4; and
(h) water qs to 100%.
The water content of the composition of the present invention is critical. Water is necessary to dissolve the chelating agent(s) present in the composition. Water also acts as a moisturizer. Deionized or purified water is preferred.
The amount of water present in the composition must be sufficient to dissolve the chelating agent(s) present in the composition. The composition preferably contains at least 12% water, more preferably, at least 15% water, most preferably at least 20% water.
The chelating agent is an essential component of the composition of the invention as it is necessary to the stability of the tretinoin component.
Any pharmaceutically acceptable acid can be employed as the acidulant, for example, hydrochloric acid, phosphoric acid and citric acid. Citric acid and phosphoric acid are preferred as they also finction as chelating agents. Thus, when citric acid, phosphoric acid or a mixture of citric acid and phosphoric acid is employed as a chelating agent in the composition of the invention, the need for an acidulant may be obviated.
The antioxidant is another essential component of the composition of the invention. The termxe2x80x9cantioxidantxe2x80x9d is understood by those skilled in the art as encompassing the finctions of reducing, free radical chain terminating and oxygen scavenging. With this in mind, the antioxidant employed in the composition of the present invention is selected from the group consisting of butylated hydroxyannisole (xe2x80x9cBHAxe2x80x9d), butylated hydroxytoluene (xe2x80x9cBHTxe2x80x9d), ascorbic acid, ascorbyl palmitate, lecithin, norhydroguaiaretic acid, propyl gallate, a-tocopherol, sodium bisulfite, cysteine, sodium metabisulfite, thioglycerol, thioglycolic acid and thiomersal.
It should be understood that the selection of the antioxidant from the aforementioned group must satisfy the requirement that at least two of the functions of oxygen scavenging, free radical chain terminating and reducing are provided. Preferably the two functions that are provided are oxygen scavenging and free radical chain terminating. Thus, BHT, ascorbic acid, ascorbyl palmitate and mixtures thereof are preferred antioxidants.